Browsing by Author "Moodley, Prashini."

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The activity of nybomycin against mycobacterium tuberculosis.
(2018) Niehaus, Abraham Johannes.; Moodley, Prashini.; Sturm, Adriaan Willem.
Nybomycin was discovered in 1955, but was never developed for clinical use. The compound was noticed again in recent years when it displayed bactericidal activity against certain fluoroquinolone-resistant bacterial species. The work presented here aims chiefly at describing the effect of nybomycin on Mycobacterium tuberculosis. The study is made up of three parts. In the first part, in vitro nybomycin susceptibility testing was conducted with various fluoroquinolone-susceptible and fluoroquinolone-resistant bacterialspecies. All M. tuberculosis isolates displayed low nybomycin inhibitory concentrations regardless of fluoroquinolone resistance. Similar susceptibility results were obtained for N. gonorrhoeae isolates, but results obtained with other bacterial species were less promising. In the second part, in silico investigations were conducted to elucidate the mechanism of action of nybomycin in M. tuberculosis. Results show that nybomycin binds to M. tuberculosis gyrase enzyme with an affinity at least similar to that of fluoroquinolones. No clear differences in binding affinity were observed when gyrA mutations, commonly associated with fluoroquinolone resistance, were considered. The results suggest that the mechanism of action of nybomycin against M. tuberculosis involves inhibition of gyrase enzyme. In the third part, M. tuberculosis mutants with increased nybomycin minimum inhibitory concentrations were selected and compared with the wild type organism through whole genome sequencing. None of the isolates harbored any mutations commonly linked to known drug resistance mechanisms. This indicates that M. tuberculosis likely employs a novel mechanism of resistance against nybomycin. This may further signify that nybomycin has an additional mechanism of action against M. tuberculosis, besides the action on gyrase enzyme, as suggested by the in silico results from this study. Twenty-two genes were identified through whole genome sequencing that may potentially be linked to the mechanism of resistance and possibly an additional mechanism of action.
Antibiotic resistance in mycobacterium tuberculosis : the role of genetic mutations in resistance conferring genes and efflux transporters.
(2016) Dookie, Navisha.; Moodley, Prashini.
Two decades after the World Health Organisation (WHO) declaration of tuberculosis (TB) as a global emergency, the disease remains a public health crisis of epic proportions. The emergence of drug resistant strains of Mycobacterium tuberculosis, the etiologic agent of TB, and the convergent human immunodeficiency virus (HIV) epidemic places a devastating burden on an already weakened public health care system in South Africa. Rapid and accurate detection of drug resistance to first and second line drugs to guide effective treatment of TB is central to control of the disease and in preventing further dissemination of drug resistant strains. Knowledge of the underlying resistance mechanisms driving drug resistance in M.tuberculosis is pivotal in the design of rapid molecular based assays and will impact of the development of novel drugs and regimens for the disease. The manuscript in chapter 2 of this thesis, entitled Dynamics of antimicrobial resistance in Multi-Drug and Extensively Drug resistant strains of Mycobacterium tuberculosis in KwaZulu-Natal, South Africa, demonstrated the diversity of the resistance mechanisms amongst the multidrug resistant (MDR) TB strains currently circulating in the KwaZulu-Natal province of South Africa by the analysis of the rpoB, katG, inhA, pncA and embB genes associated with resistance to key drugs used in the treatment of TB. Multiple drug resistance mechanisms in the MDR-TB isolates suggests that the strains emerged separately and acquired resistance mutations independently. The findings of this study also confirms the clonality of the XDR-TB epidemic demonstrated by the predominance of the F15/LAM4/KZN strain family and reveals that MDR-TB strains are evolving and spreading via transmission. The manuscript in chapter 3 of this thesis, entitled Streptomycin resistance in the F15/LAM4/KZN strain of Mycobacterium tuberculosis is mediated by lineage-specific alteration of the gidB gene, demonstrated that streptomycin (STR) resistance in the F15/LAM 4/KZN MDR and XDR-TB strains was mediated by a rare, 130bp deletion within the gidB gene of M.tuberculosis leading to a complete disruption of the gene. Classical mutations in the rpsL gene mediated STR resistance in the remaining strain families. Widespread STR resistance has resulted in the exclusion of the drug from current treatment regimens. The findings of this study support the decision of policymakers and cautions the application of the drug in the absence of drug susceptibility testing. The manuscript in chapter 4 of this thesis, entitled Moxifloxacin resistance in the F15/LAM4/KZN extensively drug-resistant strain of Mycobacterium tuberculosis, demonstrated that the F15/LAM4/KZN XDR strain harboured the A90V gyrA mutation associated with high level ciprofloxacin (CPX) and ofloxacin (OFX) resistance and correlated with increased minimum inhibitory concentrations (MIC) for moxifloxacin (MXF). The results of this study cautions the utilization of MXF as part of empiric treatment protocols in the absence of moxifloxacin MIC data of the circulating XDR strains in an area. It also raises concerns regarding the regarding the use of moxifloxacin in KwaZulu-Natal. Furthermore, the current breakpoint defining resistance to MXF is of concern and requires revision. The manuscript in chapter 5 of this thesis, entitled Evaluation of Capreomycin in the treatment of the F15/LAM4/KZN extensively drug-resistant strain of Mycobacterium tuberculosis demonstrated that the A1401G rrs mutation was the main mechanism mediating resistance to the aminoglycosides, kanamycin (KAN) and amikacin (AMIK); and to capreomycin (CAP). CAP was reintroduced into TB treatment protocols without prior drug susceptibility testing. This results of this study demonstrates high level resistance to CAP and urges careful consideration in the application of CAP the KwaZulu-Natal province. Furthermore, concerns regarding the high breakpoint value that defines CAP resistance as compared to wild-type MICs for the drug results in misdiagnosis of resistance that results inadequate patient treatment and amplifies resistance. The manuscript in chapter 6 of this thesis, entitled KZN Multidrug and Extensively drug resistant strains of Mycobacterium tuberculosis remain susceptible to Linezolid and para-Amino salicylic Acid, demonstrated that the mechanisms most commonly associated with resistance to the linezolid (LIN) and para-amino salicylic acid (PAS) were absent in the MDR and XDR-TB strains in this study. Mutations detected in the drug targets were lineage specific markers rather than resistance mechanisms. This study also highlights the poor understanding of resistance to these drugs and the need for further study to allow for resistance detection to be incorporated into diagnostic assays, thus prolonging the utility of these drugs. The manuscript in chapter 7 of this thesis, entitled Efflux mediated drug resistance in clinical isolates of Mycobacterium tuberculosis in KwaZulu-Natal, South Africa, demonstrated the role of efflux pumps in mediating low level resistance. The results of this study supports the hypothesis that efflux activity leads to decreased intracellular antibiotic concentrations, thereby allowing the survival of a sub-population of bacteria under the sub-inhibitory level of the antibiotic, from which resistant mutants emerge, leading to clinically significant levels of resistance. The results of this study strongly supports the application of efflux pump inhibitors as adjunctive to the current treatment protocols. The results emanating from this thesis has contributed to the body of knowledge of drug resistance in M.tuberculosis, especially in the KwaZulu-Natal province of South Africa. Furthermore, the results can be used to guide treatment protocols and contributes to the future development of molecular based assays aimed at detecting resistance.
Beta-lactamase mediated resistance in Salmonella spp. at a tertiary hospital in KwaZulu-Natal.
(2008) Govinden, Usha.; Essack, Sabiha Yusuf.; Sturm, Adriaan Willem.; Moodley, Prashini.
Extended spectrum (3-lactamases (ESBLs) were characterized in Salmonella spp. isolates from a pediatric ward of a hospital in Durban. Forty one Salmonella spp. were subjected to serotyping, antibiotic susceptibility testing, E-Tests for ESBL detection, iso-electric focusing, polymerase chain reaction for detection of genes and sequencing. Isolates were screened for the presence of WaTEM, WaSHV, WaCTX-M, WaOXA , WaCMY, WaDHA and WaACC genes. The most common serotype was Salmonella Typhimurium. Isolates were multi-drug resistant with 100% susceptibility only to meropenem and ciprofloxacin. Tazobactam was the most effective inhibitor. Forty-one percent of the isolates were resistant to ceftriaxone, thus limiting therapeutic options for Salmonella infections.TEM-1 was the most predominant (3-lactamase found in 51% of isolates while SHV-12 found in 39 % was the most common ESBL. TEM-63 was evident in 29 %, TEM-116 in 10 % and TEM-131 was found in one isolate. The high ceftazidime MICs of isolates expressing only TEM-63 were indicative of R164S substitution which widens the binding cavity to accommodate the bulky side chains of oxyiminoaminothiazolyl cephalosporins. The identification of TEM-131 which differs from TEM-63 by 1 amino acid reiterates the evolutionary potential of the TEM-type plactamase. Other ESBLs identified included SHV-2, CTX-M-3, CTX-M-15 and CTX-M-37. CMY-2 and the OXA-1 p-lactamase were also detected. This is the first report of TEM-116, CTX-M-3, -15 and -37 in Salmonella spp. in South Africa. All isolates with nalidixic acid MICs > 48 ug/ml had the mutation D87N, or D87G in the QRDR of the gyrA gene. This study showed that Salmonella spp. may be multi-drug resistant with the propensity to harbour p-lactamases in unique combinations. The diversity of ESBLs and the co-expression of quinolone resistance suggests that their incidence in salmonellae needs to be monitored.
Detection of carbapenem-resistant Enterobacteriaceae amongst neonates in a regional hospital in KwaZulu-Natal : screening for carbapenemase production and MIC correlation.
(2014) Govender, Kathleen.; Moodley, Prashini.
Carbapenemases are the primary cause for the increase in carbapenem resistance in Gram- negative Enterobacteriaceae. These enzymes are β-lactamases and have the ability to hydrolyse almost all β-lactam antibiotics thereby inactivating carbapenems that are used for the treatment of severe nosocomial infections. Multiple CPE outbreaks and epidemics have been reported in several hospitals in South Africa since the year 2011. This resulted in an increase in the morbidity and mortality rates and are slowly disseminating globally among more vulnerable individuals including neonates. Therefore, the aim of the study was to determine appropriate techniques for the rapid detection of carbapenem-resistant Enterobacteriaceae (CRE) (including CPE) isolated from neonates from King Edward VIII Hospital as well as to determine the molecular mechanisms conferring carbapenemase production in this subset of isolates. A total of 94 Klebsiella pneumoniae and 41 Enterobacter cloacae samples were isolated in this study. Among these species 10 % (9/ 94) and 39 % (16/ 41) of K. pneumoniae and E .cloacae respectively, were resistant to the carbapenems based on the Kirby-Bauer susceptibility tests, microbroth-dilution and E-tests. However, screening for carbapenemase production using chromogenic agar (Brilliance™ CRE agar and ChromID® CARBA agar), Modified Hodge test and amoxycillin-clavulanate double disc synergy test did not correlate with these resistance patterns and exhibited false positive results possibly due to the presence of extended spectrum beta-lactamase (ESBL) production by these organisms. Due to such discrepancies in the phenotypic results, further detection for the presence of carbapenemases was performed using multiplex real-time PCR assays. This revealed the presence of the blaOXA-48 gene in only 1 K. pneumoniae isolate. Further molecular characterisation will be required to determine if alternate mechanisms of resistance are present in the resistant isolates detected in this study.
Drug susceptibility testing of second and third line anti-tuberculosis drugs used in the management of extensively drug resistant tuberculosis.
(2013) Moodley, Salona.; Moodley, Prashini.
Drug resistant tuberculosis is a major contributor to South Africa’s quadruple burden of disease. Management of this infection in a highly HIV endemic area is a constant challenge. There is a paucity of new anti-tuberculosis agents in the developmental and clinical trial phases to address the problem of extensively-drug resistant tuberculosis (XDR-TB). In an attempt to affect a cure in patients with XDR-TB, it has become necessary to re-introduce previously used anti-tuberculosis drugs, as well as antimicrobial agents designed for treatment of non-tuberculosis infections. Whilst these drugs may have previously been tested and shown efficacy in drug susceptible tuberculosis, their activity in XDR TB strains was not tested before introduction for management of XDR-TB in KwaZulu-Natal, South Africa. Drug susceptibility testing (DST) plays an integral role in the diagnosis and treatment options for tuberculosis. It is able to decrease the burden and spread of resistant tuberculosis. However DSTs methods for second line anti –TB drugs (SLDs) and third line anti-TB drugs (TLDs) have not been standardised. Critical concentrations of these anti-TB drugs remain unknown or vary within and between settings thus further hampering the control of TB.
Drug susceptibility testing of second and third line anti-tuberculosis drugs used in the management of extensively drug resistant tuberculosis.
(2013) Moodley, Salona.; Moodley, Prashini.
Drug resistant tuberculosis is a major contributor to South Africa’s quadruple burden of disease. Management of this infection in a highly HIV endemic area is a constant challenge. There is a paucity of new anti-tuberculosis agents in the developmental and clinical trial phases to address the problem of extensively-drug resistant tuberculosis (XDR-TB). In an attempt to affect a cure in patients with XDR-TB, it has become necessary to re-introduce previously used anti-tuberculosis drugs, as well as antimicrobial agents designed for treatment of non-tuberculosis infections. Whilst these drugs may have previously been tested and shown efficacy in drug susceptible tuberculosis, their activity in XDR TB strains was not tested before introduction for management of XDR-TB in KwaZulu-Natal, South Africa. Drug susceptibility testing (DST) plays an integral role in the diagnosis and treatment options for tuberculosis. It is able to decrease the burden and spread of resistant tuberculosis. However DSTs methods for second line anti –TB drugs (SLDs) and third line anti-TB drugs (TLDs) have not been standardised. Critical concentrations of these anti-TB drugs remain unknown or vary within and between settings thus further hampering the control of TB.
The effect of HIV and Neisseria gonorrhoeae on the tight junctions of cervical epithelial cells.
(2020) Maharaj, Shevani.; Sturm, Adriaan Willem.; Moodley, Prashini.
Introduction: Neisseria gonorrhoeae and HIV are major public health concerns globally. The interaction between these diseases is unclear. To determine the effect that N. gonorrhoeae and HIV have on the tight junctions of cervical epithelial cells, a cervical epithelial cell line was infected with N. gonorrhoeae only, HIV only and with N. gonorrhoeae and HIV simultaneously. Methods: The ME180 cervical cell line was grown to confluence and infected withN. gonorrhoeae only, HIV only and with N. gonorrhoeae and HIV simultaneously. Following infection, N. gonorrhoeae and HIV tansmigration assays and the blue dextran permeability assay were also performedto determine the effect that exposure to the microbes would have on the intact cervical epithelial layer. The tight junction gene expression assays, blue dextran permeability assay and immunofluorescence staining was performed to determine the effect that exposure to the different microbes had on the tight junctions. Results: The results of this study showed that exposure of the cervical epithelial layer to N. gonorrhoeae alone, HIV alone and to N. gonorrhoeae and HIV simultaneously did not affect the paracellular permeability of the epithelial layer. The results showed that a small percentage of N.gonorrhoeaeand HIV was able to migrate across the epithelial layer. With the simultaneous infection of N.gonorrhoeae and HIV, the presence of HIV did not seem to influence the migration of N. gonorrhoeae, as compared to infection with N. gonorrhoeae only, while the presence of N.gonorrhoeae seemed to cause the HIV to pass through the epithelial layer less efficiently than with exposure to HIV only. Discussion: The overall results suggest that since exposure to these microbes does not seem to affect the tight junctions of the intact epithelial layer and does not affect the paracellular permeability, the migration of the microbes across the epithelial layer was possibly through transcytosis.
Effectiveness of a monovalent human rotavirus vaccine among children of 5 years and under in KwaZulu-Natal.
(2016) Asowata, Osaretin Emmanuel.; Moodley, Prashini.
Human rotavirus infection is the leading cause of gastroenteritis in infants and young children worldwide. In South Africa, gastroenteritis is a major cause of childhood morbidity and mortality in children less than 5 years, and rotavirus infection has been documented as causing one-third of all gastroenteritis related hospital admissions. Vaccination is the major public health intervention to control rotavirus disease. The Rotarix® is the only rotavirus vaccine included in the national immunization program of South Africa. The effectiveness of this vaccine is questionable due to the continual outbreaks of rotavirus infection in South Africa, including KwaZulu-Natal, regardless of the high vaccination coverage. This study focused on evaluating the factors influencing the effectiveness of the Rotarix® vaccine in children 5 years and under in KwaZulu-Natal, South Africa. After obtaining written informed consent from parents or guardians, stool and blood specimens where collected from children 5 years and under presenting to King Edward VIII hospital (KEH VIII) in Durban, South Africa. The study was conducted between June 2014 and June 2015. Demographic and clinical information was collected using a well-structured questionnaire. Enzyme immunoassay (EIA) was performed to detect rotavirus antigen in the stool and rotavirus immunoglobulin G (IgG) in the serum. Selected EIA positive and negative samples were confirmed using G-types and P-types consensus primers in a Reverse Transcriptase Polymerase Chain Reaction (RT-PCR). The RT-PCR positives were genotyped using genotypes specific primers. The avidity of the rotavirus specific IgG was determined using the urea elution technique. Rotarix® vaccines stored at optimum temperatures were collected from the provincial pharmaceutical store. The effect of sub-optimal temperatures on the potency of the Rotarix® vaccine were determined using the plaque assay. Three hundred and sixty-five (365) stool specimens were collected. Rotavirus antigen was detected in 83 (22.7%) patients from stool specimens. The stratification of rotavirus cases by vaccination status was not significant (p=0.4). The distribution of rotavirus was not significantly associated with HIV status of the children (p=0.7). We observed that seasonality was a significant driving force influencing the prevalence of rotavirus infection in our setting (p<0.001). We recorded the highest rotavirus prevalence in the winter months of the year with 79 (45.9%) positive cases of rotavirus associated diarrhoea. Blood specimens were only collected in 35 patients. From the corresponding stool specimens [21 (60%) EIA positives and 14 (40%) EIA negatives)], 29 (82.9%) were positive for rotavirus using conventional RT-PCR. Genotyping revealed G9P[8] (20.7%) to be the most prevalent genotype followed by G9P[4] (13.8%), G12P[4] (10.3%), G9P[6] (6.9%) and a 3.4% prevalence was recorded for each of G4/G8P[6], G4P[6], G12P[6], G8P[10] and G9P[10]. We were unable to fully genotype some of the rotavirus strains (non-typeable) by the available primers. 2 (6.9%) and 4 (13.8%) were non-typeable for the G and P types respectively. However, all 35 serum samples were positive for rotavirus IgG. We observed that the rotavirus specific IgG had no significant effect on the prevalence of rotavirus detection in stool (p=0.8). There was no significant difference in the mean avidity of IgG in the 3 vaccination strata (p=0.3). Exposure of the Rotarix® vaccine to the seasonal temperatures and to extreme temperatures of 40oC for 3 to 72 hours as well as -20oC and -80oC for 12 hours did not affect the potency of the vaccine beyond its expected standard. Our study highlighted the genetic diversity of rotaviruses and poor immunogenicity of the vaccine as key factors affecting the effectiveness of the rotavirus vaccine. Whether the vaccine is able to induce homotypic and heterotypic protection in immunized children is critical in predicting the long range effectiveness of this vaccine against uncommon regional rotavirus strains. Interventions targeted at improving socio-economic conditions in low income countries might be a starting point towards the control and prevention of rotavirus infection in these settings.
High prevalence and incidence of asymptomatic sexually transmitted infections during pregnancy and postdelivery in KwaZulu Natal, South Africa.
(Wolters Kluwer., 2015) Moodley, Dhayendre.; Moodley, Prashini.; Sebitloane, Hannah Motshedisi.; Soowamber, Deepak.; McNaughton-Reyes, Heather Luz.; Groves, Allison K.; Maman, Suzanne.
Abstract available in pdf.
HIV and hepatitis B/C co-infection in KwaZulu-Natal from 2002 to 2010 : a retrospective database analysis.
(2015) Tathiah, Nerisha.; Bagwandeen, Chauntelle Ingrid.; Moodley, Prashini.
Introduction Sub-Saharan Africa has the highest Human Immunodeficiency Virus (HIV) prevalence and the second highest Hepatitis B virus (HBV) and Hepatitis C virus (HCV) prevalence in the world. Co-infection of HIV, HBV and HCV occurs due to shared transmission routes and common risk factors. Existing studies from sub-Saharan Africa show wide variations in the prevalence of co-infections, depending on age, gender, race and geographical area. Aim The aim of this study was to describe HIV and HBV/HCV co-infections in KwaZulu-Natal from 2002 to 2010 using a laboratory database. Methods An observational, analytical, retrospective study design was used. The study setting was the National Health Laboratory Service Department of Virology, in Durban. The study population consisted of 507 834 individuals (all those with HIV, HBV or HCV test results from 2002 to 2010 recorded in the database). Results The overall sero-prevalence of HIV was 47%, HBV:12.05% and HCV:4.13%. The highest sero-prevalence of HIV and HCV was in the 30-35 year age group; for HBV it was in the 20-25 year age group. HIV sero-prevalence was higher in females, while HBV and HCV sero-prevalence was higher in males. The uThukela, Amajuba and Zululand health districts had the highest HIV, HBV and HCV sero-prevalence respectively. The sero-prevalence of HIV and HBV has decreased significantly over time, while there was no significant change in the sero-prevalence of HCV. Compared to those without HIV, individuals with HIV had increased odds of being positive for hepatitis markers: 3.19 for Hepatitis B surface antigen, 2.06 for Hepatitis B e antigen and 2.91 for HCV. Those with HIV were less likely to be positive for Hepatitis B surface antibodies. Those with Hepatitis B had a 1.38 times the odds of being co-infected with HCV compared to those without HBV. Discussion This study documented the high sero-prevalence of HIV, HBV and HCV over 9 years for KwaZulu-Natal. A significant number of HIV positive individuals are co-infected with either HBV or HCV. Recommendations The results of this study may guide public health decisions on the approach to diagnosis, treatment and prevention of HBV and HCV among those with HIV.
Immunopathogenesis of vulvo-vaginal candidiasis in human immunodeficiency virus infected women.
(2014) Apalata, Teke.; Moodley, Prashini.
Vulvovaginal candidiasis (VVC) is an important cause of lower genital tract infections in women. There are currently numerous clinical observations linking increased cases of symptomatic VVC to the progression of HIV epidemic. While the pathogenesis of other commonly encountered mucosal candidiasis (oral and oesophageal) in the context of HIV infection has been well studied, gaps in our knowledge remain regarding candida vaginitis. With increasing degree of immunosuppression, symptomatic VVC in HIV infected women is frequent, severe, recurrent and less responsive to conventional anti-fungal therapy. The quality of life is greatly diminished for women who experience recurrent episodes of symptomatic VVC. Furthermore, the high prevalence of HIV infected women adds to the burden of healthcare. In this study, we sought to further understand the pathogenesis of symptomatic VVC and the associated host defense mechanisms in HIV infected women. The results of this study are presented as a collection of 5 papers, 4 of which are published in peer reviewed journals, 1 is still under review. The initial chapter of this thesis, ‘Introduction and Background’, is followed by the 5 manuscripts which are grouped into 3 consecutive result chapters as follows: I. Impact of HIV on symptomatic VVC. II. Impact of symptomatic VVC on HIV RNA levels in plasma and genital secretions. III. Plasma and vaginal-associated immune responses in women with symptomatic VVC. The final chapter, ‘Discussion and Conclusions’, rounds up the thesis.
Improving the efficacy of bacillus calmette guerin vaccine by concomitant inhibition of T regulatory and T helper 2 cells.
(2015) Kumar, Santosh.; Moodley, Prashini.; Das, Gobardhan.
Tuberculosis (TB) remains a major threat to human population as currently Mycobacterium tuberculosis (MTB) infects nearly 33% of the global population. Annually, about one and a half million deaths are caused by tuberculosis (TB). Current reports suggest that approximately nine million new TB cases are reported every year. There is an available therapy for TB, however it is quite lengthily and consists of numerous antibiotics leading to treatment dropout. This treatment incompletion has been linked to the major cause for the appearance of drug-resistant species of MTB. Consequently, alternate therapies to treat TB are needed. Bacillus Calmette-Guerin (BCG) remains the only vaccine of choice since its inception in 1921. Although BCG mounts host protective T helper1 (Th1) cell activation, which plays a pivotal role in host protection against TB, its efficacy is inadequate, suggesting that additional methods to enhance protective immune responses are needed. We have also shown that simultaneous inhibition of Th2 cells and Tregs by using pharmacological inhibitors (suplatasttosylate and D4476, respectively) dramatically enhance MTB clearance and induces a superior Th1 response. Here we show that treatment with these two immuno-modulators during BCG vaccination dramatically improves vaccine efficacy. Furthermore, we demonstrate that these drugs induce a shift in T cell memory development, towards central memory T (Tcm) cell responses. Collectively, our findings provide evidence that concurrent inhibition of T helper cells type 2 and Tregs during BCG vaccination promotes vaccine efficacy.
Molecular characterization of the tetM gene in clinical isolates of neisseria gonorrhoeae in KwaZulu-Natal, South Africa.
(2017) Rambaran, Santhuri.; Moodley, Prashini.
Abstract available in PDF file.
Nosocomial transmission of Mycobacterium Tuberculosis in a regional hospital
(2017) Msizi, Lungile.; Moodley, Prashini.
Nosocomial transmission of drug resistant tuberculosis is well-documented in South Africa. The level of risk varies by patient population and effectiveness of M.tb infection control measures. The risk is higher in places where large numbers of infectious M.tb patients are being treated, particularly in the absence of other infection control measures such as respiratory protection. Globalization has led to the exchange and circulation of the various strains worldwide, leading to greater global diversity of M.tb strains. This ultimately increased the risk of individuals being infected with more than one strain at a time ie; having mixed infection Methodology In this study, we investigated the extent of transmission of drug resistant M. tuberculosis between patients hospitalized in a specialized TB hospital. The study was carried out at the FOSA TB hospital, Durban, South Africa. Genotyping was performed using IS6110-RFLP and spoligotyping. Results A total of 52 patients were recruited, from which 28 isolates were successfully cultured and genotyped. Cluster analysis of the isolated genotypes suggests nosocomial transmission of drug resistant strains amongst the in-patients. A majority of the strains found among the patients belonged to the F15/LAM4/KZN family (64%), followed by three clusters of formerly uncharacterised strains which were named Unique I, II and III. Only one of the drug resistant isolates belonged to the Beijing family of strains. Several locations and activities were identified where transmission could potentially have occurred, but this could not be done for individual patients Conclusion Implementation of rapid diagnostic testing for drug-resistant TB and redesign of healthcare facilities, to minimize congregate spaces, are critical elements that should be included in TB infection control programs; in addition to administrative, environmental and personal protective measures.
Population pharmacokinetics and pharmacodynamics of Ofloxacin in South African patients with multidrug-resistant tuberculosis.
(American Society for Microbiology., 2012) Chigusta, Emmanuel.; Meredith, Sandra.; Wiesner, Lubbe.; Padayatchi, Nesri.; Harding, Joe.; Moodley, Prashini.; MacKenzie, William R.; Weiner, Marc.; McIlleron, Helen.; Kirkpatrick, Carl M. J.
Despite the important role of fluoroquinolones and the predominant use of ofloxacin for treating multidrug-resistant tuberculosis in South Africa, there are limited data on ofloxacin pharmacokinetics in patients with multidrug-resistant tuberculosis, no ofloxacin pharmacokinetic data from South African patients, and no direct assessment of the relationship between ofloxacin pharmacokinetics and the MIC of ofloxacin of patient isolates. Our objectives are to describe ofloxacin pharmacokinetics in South African patients being treated for multidrug-resistant tuberculosis and assess the adequacy of ofloxacin drug exposure with respect to the probability of pharmacodynamic target attainment (area under the time curve/MIC ratio of at least 100). Sixty-five patients with multidrug-resistant tuberculosis were recruited from 2 hospitals in South Africa. We determined the ofloxacin MICs for the Mycobacterium tuberculosis isolates from baseline sputum specimens. Patients received daily doses of 800 mg ofloxacin, in addition to other antitubercular drugs. Patients underwent pharmacokinetic sampling at steady state. NONMEM was used for data analysis. The population pharmacokinetics of ofloxacin in this study has been adequately described. The probability of target attainment expectation in the study population was 0.45. Doubling the dose to 1,600 mg could increase this to only 0.77. The currently recommended ofloxacin dose appeared inadequate for the majority of this study population. Studies to assess the tolerability of higher doses are warranted. Alternatively, ofloxacin should be replaced with more potent fluoroquinolones.
Proliferation of klebsiella pneumoniae in medication containing vials for multiple dose medication and intravenous fluids.
(2019) Misra, Reshma.; Sturm, Adriaan Willem.; Moodley, Prashini.
Background and objectives: Klebsiella pneumoniae is frequently implicated in healthcare associated infections. This organism is non–fastidious and easily transmitted in a healthcare environment. Medication fluids are an ideal vehicle for transmission of these organisms. This study aimed to determine if K. pneumoniae would proliferate in various medication fluids. Method: The behaviour of K. pneumoniae was studied in piperacillin/tazobactam, ciprofloxacin, meropenem, insulin, heparin, lignocaine, and gentamicin, concentrations (50-2 %) of dextrose, Neonatalyte® and saline. This was assessed over a 24-hour period at 25 oC and 35 oC. Results: K. pneumoniae did not proliferate in the antibiotics or the multi-dose vials. The bacteria persisted in Neonatalyte® and saline. Bactericidal activity was observed in 50 %, 25 % and 12.5 % dextrose at both incubation temperatures. In 10 %, at 24 hours post inoculation, a decrease of 57 % and 50 % was observed at 25 oC and 35 oC respectively. At concentrations of 6 %, 3 % and 2 %, after 24 hours post inoculation at 25 oC, the colony count increased by 112 %, 124 % and 133 % and at 35 oC by 120 %, 134 % and 150 % respectively. There was no difference in the behaviour of K. pneumoniae at 25 oC and 35 oC. Neonatalyte® and saline demonstrated no increase in the cfu/mL over 24 hours. Conclusions: Persistence of the test bacteria in saline, neonatalyte and lower concentrations of dextrose has been shown. This poses serious risk to patient care if the bacteria inadvertently enter the fluid due to infection prevention breeches.
Spectinomycin resistance in Neisseria gonorrhoeae.
(2006) Sukhdeo, Samantha S.; Moodley, Prashini.
Abstract available in PDF.
Spread of multi drug resistant tuberculosis (MDR) including extensively drug resistant turberculosis (XDR TB), in rural KwaZulu-Natal.
(2011) Ramtahal, Melissa Afton.; Moodley, Prashini.
Mycobacterium tuberculosis (MTB) is an airborne pathogen that is easily transmitted from person to person. An intact immune system prevents the organism from causing disease in most individuals. In South Africa, the prevalence of human immunodeficiency virus (HIV) has reached astronomical levels and is now fuelling the tuberculosis (TB) epidemic. Drug resistant MTB strains combined with a weakened host immune system is a lethal combination. Multi-drug resistant (MDR) including extensively drug resistant (XDR) tuberculosis is on the increase, with Tugela Ferry in KwaZulu-Natal South Africa, reporting the largest cluster of XDR cases in the world. It is unknown whether a single clone of the drug resistant strain is circulating in this area or whether there are multiple strains at play. Using 2 complementary genotyping methods, we showed that the MDR strains present are the result of clonal spread associated with the F28 family, as well as de novo resistance which manifests as unique patterns. The XDR epidemic in Tugela Ferry is the result of clonal spread of a strain belonging to the F15/LAM4/KZN family.
The syndromic management of sexually transmitted diseases : clinical microbiological response in relation to aetiology, susceptibility patterns and co-infection with HIV-1 [electronic resource].
(2002) Moodley, Prashini.; Sturm, Adriaan Willem.
HIV-1 is the most prevalent and notorious sexually transmitted pathogen locally, and constantly challenges our foundation of knowledge regarding the classical STIs. The ultimate objective of the syndromic management strategy was to reduce the load of sexually transmitted infections, and hence HIV transmission. This strategy is multifaceted and not only includes the recognition of symptoms by the patient and an effective treatment regime that comprehensively covers the possible aetiological agents for a defined syndrome, but also appropriate health seeking behaviour of infected individuals, recognition of syndromes by the health care worker, partner management (notification and treatment), behavioural counselling and condom promotion. Understanding the complexity of sexual networking and transmission dynamics is part of such a strategy. So, although the rationale and design of syndromic case management appears simplistic, it is by no means easy to implement
TylA has an essential virulence role in mycobacterium tuberculosis pathogenesis.
(2015) Sobia, Parveen.; Moodley, Prashini.
Mycobacterium tuberculosis (M.tb), the causative agent of the disease tuberculosis, is an ancient pathogen and a major cause of death worldwide. Although various virulence factors of M.tb have been identified, its pathogenesis remains incompletely understood. TlyA is a virulence factor that is evolutionarily conserved in many gram-positive bacteria, but its function in the pathogenesis of infection with M.tb has not been elucidated. Here, we report that TlyA cause translocation of M.tb from phagolysosome into the cytosol in murine macrophages, which is the key to mycobacterial pathogenesis. In this study we also showed that TlyA mutant M.tb strain induces increased IL-12 and reduced IL-1β and IL-10 cytokine responses, which is in contrast to the immune responses induced by wild type M.tb. Mice infected with TlyA deficient mutant M.tb organisms exhibited increased host protective immune responses, reduced bacillary load, and increased survival compared with animals infected with wild type M.tb. Therefore it is likely that M.tb employs TlyA as a host evasion factor, thereby contributing to its virulence.